This proposal describes a five-year career development program whose goal is to prepare Dr. Vasanth Vedantham for a role as an independent investigator. This program will build on Dr. Vedantham's background as a basic electrophysiology and clinical cardiac electrophysiologist by providing expertise in molecular and developmental biology. The principal guidance will be provided by the mentor, Dr. Deepak Srivastava, Professor of Pediatrics at University of California, and Director of the Gladstone Institute of Cardiovascular Disease, an expert in developmental biology. The training plan includes structured mentorship with an advisory committee, formal coursework, and a research program which will provide thorough training in molecular and developmental biology. In his preliminary studies, Dr. Vedantham has developed and validated a set of tools to be used to study the ventricular conduction system (VCS) in mouse models. He has used these tools to explore the roles of MicroRNA-1 (miR-1), a muscle-specific microRNA, in the development and function of the VCS. This work has demonstrated that miR-1 dosage profoundly affects VCS structure and function. In the research proposal, Dr. Vedantham will build on these findings to test the hypothesis that miR-1 regulates the development and function of the VCS by participating in a set of critical gene regulatory networks. He will begin by carefully assessing architecture, cell number, and proliferation rates during VCS development in mouse models with altered miR-1 levels. He will then perform detailed studies of VCS cellular function in these mouse models. With this integrated picture of the specific ways in which VCS biology is sensitive to miR-1 levels, he will use a comprehensive set of approaches -- beginning with candidate genes -- to define the regulatory networks that mediate these effects. He will thereby uncover new biological pathways in a highly clinically relevant tissue. In addition, this work will provide a foundation for future studies on the role of miR-1 and other microRNAs in the cardiac conduction system to be carried out by Dr. Vedantham when he become an independent investigator. PUBLIC HEALTH RELEVANCE: Diseases of the cardiac ventricular conduction system are highly prevalent and can result in lethal arrhythmias including complete heart block and sudden cardiac death, major sources of morbidity, mortality, and health care expenditures in the USA. This proposal aims to delineate regulatory mechanisms in this tissue to improve understanding of conduction system disease and to facilitate the search for treatments.